HYL-7-OXO[1,2,4]TRIAZOLO[1,5-ALPHA]PYRIMIDINE)(2)] - A STERICALLY RESTRICTIVE NEW CISPLATIN ANALOG - REACTION-KINETICS WITH MODEL NUCLEOBASES, DNA INTERACTION STUDIES, ANTITUMOR-ACTIVITY, AND STRUCTURE-ACTIVITY-RELATIONSHIPS

The formation and isolation of the antitumor drug cisplatin analogue c is-[PtCl2(Hmtpo-N-3)(2)]. 2H(2)O (1) (where Hmtpo = -H-5-methyl-7-oxo[ 1,2,4]triazolo[1,5-a]pyrimidine) by reaction of Hmtpo with K-2[PtCl4] in HCl (0.5 N) is reported. This complex crystallizes in the monoclnic space group P2(1)/c with unit cell dimensions a = 15.215(2) Angstrom, b = 9.629(1) Angstrom, c = 13.115(3) Angstrom, beta = 97.40(2)degrees , and Z = 4. The molecular structure shows that Pt is in an almost squ are planar environment, PtN2Cl2, which has a cis configuration. The Hm tpo ligands show a head to head orientation in the solid state and non restricted rotation about the Pt-N bonds in solution. The reactivity o f the complex to model nucleobases 9-ethylguanine (9-EtGH) and 1-methy lcytosine (1-MeC) has been investigated by H-1 NMR spectroscopy at 45 degrees C in aqueous media. The results show that 1 reacts slowly with 9-EtGH (t(1/2) approximate to 5 days) by displacement of Cl-, produci ng cis-[Pt(mtpo-N-3)(2)(9-EtGH-N-7)(2)], which is similar to the major cross-link adduct of cisplatin with DNA. However, I gives no reaction with 1-MeC. This appears to be due to the lesser reactivity of 1-MeC and to competition between the cross-link reaction and dimerization of 1 to [Pt-2(mu-mtpo-N-3,N-4)(4)]. Circular dichroism studies of DNA in the presence of 1 show that the platinum complex reacts efficiently a fter 48 h at a optimum ratio of 0.25 Pt atom/mol of DNA nucleotide. Th ese results and those obtained from reaction of 1 with 9-EtGH suggest that the platinum compound binds the N7 atoms of two guanines of the s ame strand, forming. intrastrand cross-linked adducts. Chelation of DN A bases by 1 causes important conformational changes, bringing the gua nines close together. The anticancer activity of complex I has been te sted against the human cancer cell lines MCF-7 breast carcinoma and A1 21 ovarian carcinoma. Results indicate a moderate antitumor activity a gainst breast carcinoma and a marked and selective cytotoxic effect ag ainst ovarian carcinoma.